GENETIC REGULATION OF MELANIN BIOSYNTHESIS

描述：(改编自申请者的摘要)-黑色素是一种 主要存在于皮肤、头发和眼睛中的复杂生物聚合物。它 作为身体表面的一种光保护色素，提供 化妆品的吸引力和伪装，并参与了 眼睛和视神经。黑色素的合成始于酪氨酸和 涉及到一系列导致黑棕色真黑素或红黄色的步骤 褐黑素。酪氨酸酶，作为与其他色素酶复合体的一部分 和蛋白质因子，催化黑色素合成的前两步 途径，而酪氨酸酶活性的丧失与完全丧失有关 黑素细胞中的黑色素。 研究人员建议研究酪氨酸酶在调节中的作用 利用人酪氨酸酶相关眼皮肤白化病合成黑色素的研究 或OCA1作为模型系统。大多数酪氨酸酶基因突变与 完全缺乏黑色素(OCA1A)，而一些与 出生后头发、皮肤和眼睛中形成一些黑色素 (OCA1B)。研究人员假设OCA1B突变会产生酶 具有残留的酸度，他们认为这些特征 突变及其对酶结构和功能的影响将提供 对黑色素合成调节的洞察。 调查人员提出了三个具体目标。首先，他们会 OCA1B携带者的分子基因型特征有待进一步研究 他们对这种白化病的初步研究。他们会找出 DNA直接测序和信使核糖核酸检测酪氨酸酶基因突变 分析。其次，他们将表征OCA1B突变对 酪氨酸酶功能。单个突变将被重新创建并在 突变酶的表达研究。第三，他们将表演 重组正常和突变酪氨酸酶的结构与功能研究 酵素。纯化的抗菌链霉菌酪氨酸酶和人酪氨酸酶 将用于结晶和x射线分析以确定 该酶的三维结构和功能结构域。这些研究 将提供有关酪氨酸酶在 黑色素合成的调节及这种关键色素的功能 酵素。所获得的知识对未来的发展将是重要的 保护皮肤免受致癌影响的有效疗法 紫外线辐射，并促进正常的眼睛发育。

DESCRIPTION: (Adapted from the applicant's abstract) - Melanin pigment is a complex biopolymer found primarily in the skin, hair, and eyes. It functions as a photoprotective pigment of the body surface, provides cosmetic appeal and camouflage, and is involved in the development of the eye and the optic nerves. Melanin synthesis starts with tyrosine and involves a series of steps that lead to black-brown eumelanin or red-yellow pheomelanin. Tyrosinase, as part of a complex with other pigment enzymes and protein factors, catalyzes the first two steps in the melanin synthetic pathway, and the loss of tyrosinase activity is associated with a total loss of melanin in the melanocyte. The investigators propose to study the role of tyrosinase in the regulation of melanin synthesis using human tyrosinase-related oculocutaneous albinism or OCA1 as the model system. Most tyrosinase gene mutations are associated with a total lack of melanin (OCA1A) while a number are associated with the formation of some melanin pigment in the hair, skin, and eyes after birth (OCA1B). The investigators hypothesize that OCA1B mutations produce enzymes with residual acidity, and they feel that the characterization of these mutations and their effect on enzyme structure and function will provide insight into the regulation of melanin synthesis. The investigators propose three specific aims. First, they will characterize the molecular genotype of individuals with OCA1B to extend their initial studies of this type of albinism. They will identify responsible tyrosinase gene mutations by direct DNA sequencing and by mRNA analysis. Second, they will characterize the effects of OCA1B mutations on tyrosinase function. Individual mutations will be recreated and analyzed in expression studies of mutant enzyme. Third, they will perform structure:function studies of recombinant normal and mutant tyrosinase enzyme. Purified Streptomyces antibioticus tyrosinase and human tyrosinase will be used for crystallization and x-ray analysis to determine 3-dimensional structure and functional domains of the enzyme. These studies will provide fundamental information on the role of tyrosinase in the regulation of melanin synthesis and the function of this critical pigment enzyme. Knowledge gained will be important for future development of effective therapy for the protection of the skin from the oncogenic effects of ultraviolet radiation, and for promoting normal ocular development.